Thyroid Metastasis from Primary Breast Cancer

Breast cancer (BC), the most commonly diagnosed malignancy, frequently metastasizes to the bone, lungs, brain and liver at advanced stages, whereas the thyroid gland represents a rare target site for secondary disease. We examined the most recent literature about thyroid metastasis (TM) from BC after we encountered a peculiar case of a 71-year-old woman who developed sudden dysphagia, severe hypothyroidism and hypoparathyroidism due to TM 18 years after the diagnosis of her primary cancer. Based on published data, the prevalence of TM in BC ranges from 3% to 34%, with a median onset time of 48.2 months, although longer time intervals are not infrequent. TM negatively impacts the prognosis of these patients, however thyroid surgery can limit the local disease burden. Therefore, we suggest that clinicians involved in the follow-up care of BC patients should consider a differential diagnosis of secondary thyroid malignancy when incidental lesions are diagnosed during radiological evaluations or local symptoms affect the cervical region, even many years after the diagnosis of the primary cancer.


Introduction
Breast cancer (BC) remains the most commonly diagnosed malignancy and the second highest cause of cancer-related mortality worldwide [1]. Bones and visceral organs, such as the lungs, brain and liver, are common target sites for metastatic BC [2]. Although the thyroid has one of the highest blood supplies (4 to 6 mL/min/g) [3], metastatic carcinoma to the thyroid is rare, and it is generally derived from primary tumors of the kidney, gastrointestinal system, lungs, skin, and, rarely, breast [4]. The presence of thyroid metastasis (TM) usually implicates a poor prognosis [5,6]. However, the improvement of diagnostic methods and cancer therapies, and the subsequent improvement in terms of the survival rate of patients, has led to a rise in the incidence of thyroid metastatic cancers [4]. Here, we report a rare case of a patient with breast cancer metastasis to the thyroid gland which became overt due to severe dysphagia, and symptomatic hypothyroidism and hypocalcemia 18 years after the primary cancer diagnosis. Moreover, to improve the management of this uncommon but potentially lethal diagnosis, we review the evidence regarding the clinical diagnosis and treatment of TM from BC.

Methods
We performed a comprehensive review of the English-language literature published between January, 2000 and the end of January, 2023, extracted from the PubMed/Medline database, on studies about patients who developed TM after a diagnosis of BC. We included original articles, reviews, opinion pieces, commentaries, case series and case reports. The search terms, used both separately and in combination, included: "thyroid metastasis", "secondary thyroid cancer", "secondary thyroid malignancy", "breast cancer", and "breast malignancy." Papers focused on metastasis of thyroid cancer and articles published in languages other than English were excluded.

Our Experience
A 71-year-old lady came to our attention due to fatigue and worsening dysphagia, first to solids and then also to liquids. She had a history of left BC, diagnosed 18 years prior and treated with a quadrantectomy and axillary lymphadenectomy, followed by chemotherapy (Adriamycin 60 mg/mq and Cyclophosphamide 600 mg/mq for four cycles), radiotherapy and hormonal therapy (Tamoxifen followed by Anastrozole for five years). At the time, the histopathology disclosed a 2 cm invasive ductal carcinoma, moderately differentiated (G2) with concomitant homolateral axillary lymph nodes metastasis (T1N1M0). Her past medical history also included hypertension, osteopenia and osteoarthritis with a Baker's cyst in the right knee.
During the work-up for dysphagia, high TSH values were found (TSH 70 mUI/L, normal range 0.27-4.20 mUI/L), while the patient's results indicated euthyroid during previous laboratory investigations (at least three measurements were taken in the year prior and were found to be within the normal limits, see Table 1). The family history did not reveal any noteworthy thyroid pathologies. The physical examination of the neck showed the presence of palpable nontender bilateral thyroid nodules. The brain MRI excluded the neurologic etiology of dysphagia, while a contrast esophagram documented a hypertonic dyskinesia at the cervical-dorsal passage, with the absence of intrinsic organic lesions. At our department, the repeated thyroid function test (TSH 27.7 mUI/L [0. , fT3 2.55 ng/L [2.5-70.70], fT4 0,92 ng/dL [0.70-1.70]) confirmed overt hypothyroidism; the levels of thyroglobulin, calcitonin and anti-thyroglobulin antibodies were normal, however there was a weak positive result for anti-thyroperoxidase antibodies (35 UI/mL, range of normal up to 10). We also detected low calcium levels (7.2 mg/dL, [8.6-10.2]) with inappropriate parathyroid hormone (PTH) levels in the lower-end of normal range (12 ng/L, ), consistent with primary hypoparathyroidism. An ultrasound of the neck was then performed which found a multinodular, but normal-sized, thyroid gland. In particular, a hypoechoic right midlobar nodule, inhomogeneous with multiple calcifications of 27 × 18 × 16 mm, and a left isoechoic inhomogeneous midlobar nodule with multiple small calcifications of 21 × 9 ×11 mm ( Figure 1) were reported. The vascularization of the thyroid parenchyma by power Doppler ultrasonography was not significantly altered, and the nodules showed perinodular vascularization. Finally, no cervical lymphadenopathy was detected.
inhomogeneous with multiple calcifications of 27 × 18 × 16 mm, and a left isoechoic inhomogeneous midlobar nodule with multiple small calcifications of 21 × 9 ×11 mm ( Figure 1) were reported. The vascularization of the thyroid parenchyma by power Doppler ultrasonography was not significantly altered, and the nodules showed perinodular vascularization. Finally, no cervical lymphadenopathy was detected. Oral liquid levothyroxine was started at a dose of 25 mcg daily, and the Fine needle aspiration cytology (FNAC) of the larger nodule revealed cytological findings compatible with a poorly differentiated malignancy (TIR5, Italian consensus for the classification and reporting of thyroid cytology, [7]). For hypocalcemia and hypovitaminosis D, therapy with calcium carbonate, calcitriol and cholecalciferol was introduced.
The patient was then admitted to our hospital due to the further deterioration of the dysphagia and her general condition. She was submitted to a whole-body computed tomography (CT) that confirmed the extrinsic compression of the esophagus by a cervical mass located at the thyroid bed ( Figure 2), sub-clavicular and paratracheal lymphadenopathy, a hepatic focal centimeter lesion at the fourth segment, abdominopelvic effusion and diffuse bone involvement (dorsal spine, bilateral hip). One month after our first visit, she was subjected to a partial thyroidectomy with significant symptom relief. The pathology of the thyroid samples disclosed a secondary malignancy of poorly differentiated breast cancer with immunophenotypes CK7+, CK 20-, GATA3+, TTF-1-, P40-, S100-, CDX-2-, Thyroglobulin-, Pax8-, and P63-. As per the specific request of the oncologist, the biological parameters of the expression of the hormone receptors (HR) were searched, which found: estrogen receptor (ER) 90% positive, progesterone receptor (PgR) 10%, Ki-67 30% and human epidermal growth factor receptor 2 (HER2) score 1+, which is considered negative. Oral liquid levothyroxine was started at a dose of 25 mcg daily, and the Fine needle aspiration cytology (FNAC) of the larger nodule revealed cytological findings compatible with a poorly differentiated malignancy (TIR5, Italian consensus for the classification and reporting of thyroid cytology, [7]). For hypocalcemia and hypovitaminosis D, therapy with calcium carbonate, calcitriol and cholecalciferol was introduced.
The patient was then admitted to our hospital due to the further deterioration of the dysphagia and her general condition. She was submitted to a whole-body computed tomography (CT) that confirmed the extrinsic compression of the esophagus by a cervical mass located at the thyroid bed ( Figure 2), sub-clavicular and paratracheal lymphadenopathy, a hepatic focal centimeter lesion at the fourth segment, abdominopelvic effusion and diffuse bone involvement (dorsal spine, bilateral hip). One month after our first visit, she was subjected to a partial thyroidectomy with significant symptom relief. The pathology of the thyroid samples disclosed a secondary malignancy of poorly differentiated breast cancer with immunophenotypes CK7+, CK 20-, GATA3+, TTF-1-, P40-, S100-, CDX-2-, Thyroglobulin-, Pax8-, and P63-. As per the specific request of the oncologist, the biological parameters of the expression of the hormone receptors (HR) were searched, which found: estrogen receptor (ER) 90% positive, progesterone receptor (PgR) 10%, Ki-67 30% and human epidermal growth factor receptor 2 (HER2) score 1+, which is considered negative. Subsequently, anticancer therapy was started, consisting of 10 cycles of chemotherapy with Paclitaxel (80 mg/mq). The patient responded to it with a return to oral enteral nutrition, weight recovery and a substantial general clinical benefit. Furthermore, thyroid function was restored following the titration of the replacement therapy with levothyroxine, up to 100 mcg per day (Table 1), and blood calcium levels fell to within normal limits, for which the patient is currently taking 25,000 UI of cholecalciferol per month and 1 mcg per day of calcitriol. At the last CT-scan follow-up, which took place a year after the sur- Subsequently, anticancer therapy was started, consisting of 10 cycles of chemotherapy with Paclitaxel (80 mg/mq). The patient responded to it with a return to oral enteral nutrition, weight recovery and a substantial general clinical benefit. Furthermore, thyroid function was restored following the titration of the replacement therapy with levothyroxine, up to 100 mcg per day (Table 1), and blood calcium levels fell to within normal limits, for which the patient is currently taking 25,000 UI of cholecalciferol per month and 1 mcg per day of calcitriol. At the last CT-scan follow-up, which took place a year after the surgery, there was a significant improvement in the disappearance of the hepatic lesion and the stability of other metastases. The patient is currently alive and no further endocrine impairment has emerged.

Current Knowledge
Secondary malignancy of the thyroid is a rare event. To define the real rate of TM is challenging; in autopsy studies, it ranges from 1.25% to 24% [8]. In previous studies, BC has been described as a variable primary source of TM [9,10], with a prevalence ranging from 3% to 34% of all thyroid metastases [11]. A recent review estimated the frequency of BC-related TM to be 7.8%, while for renal cell carcinoma (RCC) it is 48% [12]. Currently, the etiology of thyroid metastasis from primary carcinoma is not clear. In fact, although the thyroid gland is highly vascularized, it does not represent a frequent target for systemic distant disease. One study speculated that pre-existing thyroid diseases (i.e., thyroiditis and goiter) could facilitate the initiation of TM originating from cancers of different tissues, changing the thyroid microenvironment levels of oxygen and iodine [5]. On the other hand, a previous study has shown that different BC subtypes display strong associations with sitespecific metastasis target tissues [13]. Moreover, BC and differentiated thyroid cancer (DTC) are the most common malignancies among women and endocrine cancers, respectively, and their simultaneous presentation in the same patient should raise the suspicion of synchronous primary cancers, especially in light of the shared risk factors for these two types of tumors. [14][15][16]. Rare cases of TM from BC within another primary malignant thyroid cancer ("tumor-to-tumor metastasis") have also been reported [17,18]. Previous experiences reported conflicting data about the co-existence of other metastases at the time of discovery of TM; Surov and colleagues [19] showed that TM was the unique metastasis in 76% of their patients, while Hegerova et al. [10] documented contrary data, finding that 79% of patients were also affected by metastasis in other organs. These divergent results could be partly explained by the different approaches and extensions to oncological follow-up investigations adopted by the authors.
The vast majority of TMs are metachronous [20], detected after a mean time of 2.3 years in head and neck cancers [10,21], a mean time of 9.4 years in renal cell carcinoma [22], and even after 21 years in intestinal neuroendocrine tumors [23]. In our literature review, we found 38 papers published between 2000 and the end of January 2023 that satisfied our search criteria, consisting of 58 cases of TM that originated from BC [5, 9,11,17,18,. We summarized the cases in Table 2. All the reported patients were female, as expected, and the mean age was 54.2 years. When specified (in forty-three out of the fifty-eight cases), the ductal type resulted in the most frequent histology of breast cancer (28 out of 43 cases, 65%), followed by four cases of lobular type (9.3%); five (11.6%) that were defined as invasive; two (4.6%) that were poorly differentiated; and one (2%) that was defined as "ductal and lobular", medullary, metaplastic and mucinous. Of the patients, thirty-seven out of fifty-eight (63%) had sites other than the thyroid involved with metastatic disease, especially the lungs, bones and lymph nodes, while eighteen (31%) showed solitary TM and three (6%) had no relevant data recorded. The patient we report was affected by new hepatic and secondary bone disease. The average time of onset from the primary diagnosis of BC was of 70 months, ranging from simultaneous appearance [18,24,25,44] to 180 months [5,46]. Notably, our patient demonstrated TM 18 years (216 months) after the diagnosis of BC, the largest time interval reported to date. The occurrence of TM secondary to BC does not show any peculiar age relation, and of course, has a female predilection. TM can have different modes of presentation. It usually comes to the patient's and/or the clinician's attention as a palpable neck mass, which is then confirmed through an ultrasound or CT scan; however, sometimes these thyroid nodules can cause signs and symptoms of dysphagia, hoarseness, dysphonia and pain due to local invasiveness. Our patient developed severe dysphagia that limited her food and liquids intake, with subsequent weight loss. Moreover, her profuse asthenia and weakness were also exacerbated by the severe hypothyroidism and hypoparathyroidism that arose from the substitution of both gland tissues by the TM. In fact, one year before our first visit, the patient had a documented history of normal thyroid and calcium metabolism (Table 1), with no history of hormonal or replacement therapy. Only a total thyroidectomy or eventual ablation with radioactive iodine could cause such a rapid thyroid function deterioration, and neither of these had been performed. Finally, serological and histopathological investigations ruled out autoimmune thyroiditis, which is a leading cause of chronic (not acute) hypothyroidism in our population. All of these elements made our etiopathogenetic hypothesis the most plausible. This is noteworthy, since it made our patient come to our attention and it opened the way to diagnose the secondary malignancy years after the BC treatment. There are no other cases in the literature characterized by a comparable impairment of the thyroid and parathyroid function in a similar clinical context. There was one peculiar presentation that consisted in fever, neck pain and rigidity exacerbated by swallowing in a 37-year-old woman with a three year history of BC, which was initially diagnosed as acute thyroiditis, however the authors did not report the patient's thyroid function test at the time nor on previous occasions [29].    Ultrasound is the preferred imaging approach to evaluate thyroid diseases, including TM. Previous studies [56,57] agreed that secondary thyroid neoplasms can be classified into two categories, based on ultrasonographic results: (i) diffuse type, appearing as hypoechoic lesions involving the entire gland, and (ii) nodular type, appearing as hypoechoic and hypovascularized nodular lesions. In our case, the TM appeared as bilateral hypoechoic nodules with ill-defined margins and punctate hyperechoic foci, corresponding to microcalcifications, in agreement with what had already been described by other authors in patients whose primary malignancy was BC [39,49]. Nevertheless, we missed the full extent of the disease, which caused the onset of dysphagia and glands deficiencies, underlining the limited reliability of thyroid ultrasound examination due to its rare occurrence in clinical imaging, even among skilled operators. Even the ultrasound risk stratification of malignancy, recently introduced by several scientific societies to assess thyroid nodules, can miss malignant lesions [58].
Cytologic evaluation with FNAC is the exam of choice to establish the benign or malignant nature of thyroid lesions. However, less than 0.2% of thyroid FNACs [38,39] reveal a BC metastasis, and it is generally challenging to demonstrate the origin of the primary metastatic cancer [40]. FNACs of thyroid metastatic disease from BC usually consist of malignant epithelial cells with enlarged nuclei and irregular nuclear contours [33], without intranuclear grooves and pseudoinclusions. Sometimes, the cytological samples can even mimic primary TC [38], including C cell hyperplasia and medullary thyroid carcinoma [59]. In our case, the FNAC of the thyroid showed epithelial-like cells with pronounced nuclear atypia ( Figure 3A). Cytologic evaluation with FNAC is the exam of choice to establish the benign or malignant nature of thyroid lesions. However, less than 0.2% of thyroid FNACs [38,39] reveal a BC metastasis, and it is generally challenging to demonstrate the origin of the primary metastatic cancer [40]. FNACs of thyroid metastatic disease from BC usually consist of malignant epithelial cells with enlarged nuclei and irregular nuclear contours [33], without intranuclear grooves and pseudoinclusions. Sometimes, the cytological samples can even mimic primary TC [38], including C cell hyperplasia and medullary thyroid carcinoma [59]. In our case, the FNAC of the thyroid showed epithelial-like cells with pronounced nuclear atypia ( Figure 3A). In this context, immunohistochemistry (IHC) can support a differential diagnosis between TM and primary TC, which are mostly TG, TTF-1 and PAX8 positive [60], whereas these markers are negative in secondary thyroid malignancy; ER, PR, HER2, GATA3 and GCDFP15 are peculiar of BC-derived tissues [13,61]. Historically, through the identification of hormone and other oncogene receptor status, IHC allowed clinicians to describe several BC subtypes with distinct biological behaviors. This has been translated into a very useful clinical tool and has improved therapies for BC. Furthermore, as highlighted by previous study [62], the receptor status could also be correlated to site-specific metastasis patterns. In fact, beside bone metastasis, which is observed with all subtypes, brain metastasis seems to be more frequent in HR−/HER2+ patients and liver metastasis is more frequent in HER2+ than in HER2− subtypes, while secondary lung involvement is more common in triple negative (TN) tumors [13]. Our case was ER (+), PgR (+) and HER2 (−), and this pattern In this context, immunohistochemistry (IHC) can support a differential diagnosis between TM and primary TC, which are mostly TG, TTF-1 and PAX8 positive [60], whereas these markers are negative in secondary thyroid malignancy; ER, PR, HER2, GATA3 and GCDFP15 are peculiar of BC-derived tissues [13,61]. Historically, through the identification of hormone and other oncogene receptor status, IHC allowed clinicians to describe several BC subtypes with distinct biological behaviors. This has been translated into a very useful clinical tool and has improved therapies for BC. Furthermore, as highlighted by previous study [62], the receptor status could also be correlated to site-specific metastasis patterns. In fact, beside bone metastasis, which is observed with all subtypes, brain metastasis seems to be more frequent in HR−/HER2+ patients and liver metastasis is more frequent in HER2+ than in HER2− subtypes, while secondary lung involvement is more common in triple negative (TN) tumors [13]. Our case was ER (+), PgR (+) and HER2 (−), and this pattern may be highly adaptive to the thyroid microenvironment in order to initiate organ metastasis; however, further data are needed to establish this relationship.
The presence of secondary thyroid malignancy implies a poor prognosis [62,63], especially if it is synchronous with the primary tumor [6]. Previous experiences documented that after the discovery of TM, the mean survival is three years, or six years if we take into consideration the time of the diagnosis of a primary malignancy [10].
Prospective studies on the impact of surgery for metastatic disease of the thyroid are lacking, although Romero et al. demonstrated that thyroidectomies can ameliorate the prognosis of these patients [64]. Isolated thyroidectomies have a crucial role in limiting the local disease burden in order to alleviate the potential morbidity secondary to the involvement of the upper airway [65]. Of the fifty-eight cases in our review, thirty-six (62%) displayed the adopted management strategy and of these, twenty-one (61%) were treated exclusively with surgery (fifteen (71%) with total or near-total thyroidectomy, six (29%) with partial thyroidectomy), thirteen (36%) with systemic treatments and two (5%) with both. Our patient undoubtedly benefited from the subtotal thyroidectomy, which saw the complete regression of the dysphagia in a short time, and the later systemic therapy that was also implemented.

Conclusions
BC may metastasize to the thyroid gland. The clinical onset of TM can be heterogeneous or even silent and it is often an incidental finding of investigations undertaken during the follow-up care of cancer patients. We reported a rare case of TM which had originated from BC treated 18 years earlier, which had become clinically evident with severe dysphagia, hypothyroidism and hypoparathyroidism caused by the substitution of the gland tissues by the metastasis. Therefore, it is necessary to remain vigilant on the possible appearance of this type of rare distant disease, even many years after the treatment of the primary cancer. Ultrasound of the thyroid, FNAC, IHC and surgical excision are all valid tools that can help to correctly manage these challenging cases.
Funding: This research received no external funding.

Institutional Review Board Statement:
This study was conducted in accordance with the Declaration of Helsinki. Ethical approval was not required for this study, in which results are reported as aggregate data that cannot permit identification of patients.

Informed Consent Statement:
Informed consent was obtained from all subjects involved in the study.

Data Availability Statement:
The authors confirm that the data supporting the findings of this study are available within the article.

Conflicts of Interest:
The authors declare no conflict of interest.